Ten-year mortality, disease progression, and treatment-related side effects in men with localised prostate cancer from the ProtecT randomised controlled trial according to treatment received

Background The ProtecT trial reported intention-to-treat analysis of men with localised prostate cancer randomly allocated to active monitoring (AM), radical prostatectomy, and external beam radiotherapy. Objective To report outcomes according to treatment received in men in randomised and treatment choice cohorts. Design, setting, and participants This study focuses on secondary care. Men with clinically localised prostate cancer at one of nine UK centres were invited to participate in the treatment trial comparing AM, radical prostatectomy, and radiotherapy. Intervention Two cohorts included 1643 men who agreed to be randomised and 997 who declined randomisation and chose treatment. Outcome measurements and statistical analysis Analysis was carried out to assess mortality, metastasis and progression and health-related quality of life impacts on urinary, bowel, and sexual function using patient-reported outcome measures. Analysis was based on comparisons between groups defined by treatment received for both randomised and treatment choice cohorts in turn, with pooled estimates of intervention effect obtained using meta-analysis. Differences were estimated with adjustment for known prognostic factors using propensity scores. Results and limitations According to treatment received, more men receiving AM died of PCa (AM 1.85%, surgery 0.67%, radiotherapy 0.73%), whilst this difference remained consistent with chance in the randomised cohort (p = 0.08); stronger evidence was found in the exploratory analyses (randomised plus choice cohort) when AM was compared with the combined radical treatment group (p = 0.003). There was also strong evidence that metastasis (AM 5.6%, surgery 2.4%, radiotherapy 2.7%) and disease progression (AM 20.35%, surgery 5.87%, radiotherapy 6.62%) were more common in the AM group. Compared with AM, there were higher risks of sexual dysfunction (95% at 6 mo) and urinary incontinence (55% at 6 mo) after surgery, and of sexual dysfunction (88% at 6 mo) and bowel dysfunction (5% at 6 mo) after radiotherapy. The key limitations are the potential for bias when comparing groups defined by treatment received and changes in the protocol for AM during the lengthy follow-up required in trials of screen-detected PCa. Conclusions Analyses according to treatment received showed increased rates of disease-related events and lower rates of patient-reported harms in men managed by AM compared with men managed by radical treatment, and stronger evidence of greater PCa mortality in the AM group. Patient summary More than 95 out of every 100 men with low or intermediate risk localised prostate cancer do not die of prostate cancer within 10 yr, irrespective of whether treatment is by means of monitoring, surgery, or radiotherapy. Side effects on sexual and bladder function are better after active monitoring, but the risks of spreading of prostate cancer are more common

Functional and quality of life outcomes of localised prostate cancer treatments (prostate testing for cancer and treatment [ProtecT] study)

Objective To investigate the functional and quality of life (QoL) outcomes of treatments for localised prostate cancer and inform treatment decision-making. Patients and Methods Men aged 50–69 years diagnosed with localised prostate cancer by prostate-specific antigen testing and biopsies at nine UK centres in the Prostate Testing for Cancer and Treatment (ProtecT) trial were randomised to, or chose one of, three treatments. Of 2565 participants, 1135 men received active monitoring (AM), 750 a radical prostatectomy (RP), 603 external-beam radiotherapy (EBRT) with concurrent androgen-deprivation therapy (ADT) and 77 low-dose-rate brachytherapy (BT, not a randomised treatment). Patient-reported outcome measures (PROMs) completed annually for 6 years were analysed by initial treatment and censored for subsequent treatments. Mixed effects models were adjusted for baseline characteristics using propensity scores. Results Treatment-received analyses revealed different impacts of treatments over 6 years. Men remaining on AM experienced gradual declines in sexual and urinary function with age (e.g., increases in erectile dysfunction from 35% of men at baseline to 53% at 6 years and nocturia similarly from 20% to 38%). Radical treatment impacts were immediate and continued over 6 years. After RP, 95% of men reported erectile dysfunction persisting for 85% at 6 years, and after EBRT this was reported by 69% and 74%, respectively (P < 0.001 compared with AM). After RP, 36% of men reported urinary leakage requiring at least 1 pad/day, persisting for 20% at 6 years, compared with no change in men receiving EBRT or AM (P < 0.001). Worse bowel function and bother (e.g., bloody stools 6% at 6 years and faecal incontinence 10%) was experienced by men after EBRT than after RP or AM (P < 0.001) with lesser effects after BT. No treatment affected mental or physical QoL. Conclusion Treatment decision-making for localised prostate cancer can be informed by these 6-year functional and QoL outcomes

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

Nutritional, hormonal, and environmental effects on colostrum in sows

Cet article fait suite au 9. ASAS-EAAP International Workshop on the Biology of Lactation in Farm Animals ; Indianapolis (USA) - (2008-07-07 - 2008-07-11) / SymposiumInternational audienceIt is widely recognized that an early and high intake of colostrum is a major determinant of piglet survival during the early suckling period. The production of colostrum, however, is very variable among sows and the factors affecting this variability are not well known. Factors such as number of parity and genotype do seem to influence colostrum yield and composition. The endocrine status of the sow also affects the process of colostrogenesis and changes in the sow endocrine status can have an impact on quantity and quality of colostrum produced. Indeed, induction of parturition seems to play a role. Nutrition is undoubtedly a major factor that could be used as a tool to alter colostrum composition, with fat content being the most affected. Feed ingredients, such as yeast extracts and fermented liquid feed, were recently shown to alter colostrum composition, yet more research is needed to substantiate these effects. Very few data are available on the influence of environment on colostrum production; results suggest that heat stress has negative effects on colostrum composition. Considering the importance of colostrum for the survival, growth, and immune resistance of piglets, it is obvious that research on the development of new management systems is necessary to improve yield and composition of colostrum

Nutritional and endocrine control of colostrogenesis in swine

Colostrum plays an essential role in ensuring the survival, growth and health of piglets by providing energy, nutrients, immunoglobulins, growth factors and many other bioactive components and cells. Both colostrum yield and composition are highly variable among sows, yet mechanisms and factors that regulate colostrogenesis are not fully known. Unlike sow milk yield, sow colostrum yield is not highly determined by litter size and suckling intensity but is largely driven by sow-related factors. Colostrum synthesis is under hormonal control, with prolactin and progesterone concentrations prepartum having, respectively, positive and negative influences on colostrum yield. Less is known about the endocrine control of the end of colostrogenesis in swine, which is characterized by the closure of tight junctions in the mammary epithelium and the cessation of transfer of immunoglobulin G (IgG) into lacteal secretions. Recent studies indicate that exogenous hormones may influence colostrogenesis. Inducing parturition by injecting prostaglandin F2α on day 114 of gestation in combination with an oxytocin-like molecule reduced colostrum yield, and injection of prostaglandin F2α alone either reduced colostrum yield or had no effect. Injecting a supraphysiological dose of oxytocin to sows in the early postpartum period delayed the tightening of mammary tight junctions, thereby prolonging the colostral phase and increasing concentrations of IGF-I and IgG and IgA in early milk. The development of strategies to improve colostrum composition in swine through maternal feeding has been largely explored but very few attempts were made to increase colostrum yield. This is most likely because of the difficulty in measuring colostrum yield in swine. The fatty acid content of colostrum greatly depends on the amount of lipids provided in the sow diet during late gestation, whereas the fatty acid profile is largely influenced by the type of lipid being fed to the pregnant sow. Moreover, various ingredients that presumably have immuno-modulating effects (such as fish oil, prebiotics and probiotics) increased concentrations of IgG, IgA and/or IgM in sow colostrum when they were provided during the last weeks of gestation. Finally, there is some evidence that sow nutrition during late gestation may influence colostrum yield but this clearly warrants more research. This review emphasizes that although progress has been made in understanding the control of colostrogenesis in swine, and that strategies exist to manipulate fat and immunoglobulin contents of colostrum, ways to increase colostrum yield are still lacking

Peut-on augmenter la quantité de colostrum disponible pour les porcelets naissants ?

National audienc

Relations between sow hormonal concentrations around parturition and immunoglobulin G concentrations in colostrum

Session 2 : Endocrine regulation of the mammary gland at different functional stagesInternational audienceLike most farm animals, the piglet is born devoid of systemic humoral immunity and therefore relies on maternal immunoglobulins G (IgG) provided by colostrum. Concentrations of IgG in colostrum are highly variable among sows and factors influencing them are not fully known in pigs. Although passive diffusion between mammary epithelial cells cannot be excluded, the uptake of IgG by mammary glands in pigs could be mediated by a Fc-specific receptor, the neonatal Fc receptor (FcRn), as is the case in ruminants. In cattle, the expression of FcRn could be stimulated by the decrease in progesterone/oestradiol ratio in late pregnancy and then be inhibited by the peripartum peak of prolactin. The aim of the present study was to investigate the relations between hormonal concentrations around parturition and colostral IgG concentrations in primiparous sows. Colostrum samples were collected in 40 Landrace × Large White primiparous sows at the onset of parturition (t0) and 24 h later (t24) and were assayed for IgG concentrations. Colostrum yield was estimated during 24 h starting at the onset of farrowing using piglets’ weight gains. Jugular blood samples were taken on d-8, d-2, d-1 and the day of farrowing (d0) and were assayed for prolactin, progesterone, oestradiol-17β, cortisol, IGF-I, and IgG. Amounts of IgG exported into colostrum in 24 h were estimated (colostrum yield x ([IgG] at t0 + [IgG] at t24)/2). Analyses of correlations and multiple regression were performed. Multiple regression was focussed on a subset of 20 sows because one of the most contributing variables (IgG concentrations in sow plasma) had been measured in 20 sows only. Concentrations of IgG in colostrum (means ± SD) averaged 70.5 ± 23.5 and 13.0 ± 7.4 mg/mL at t0 and t24, respectively. Concentrations of IgG in colostrum at t0 were positively correlated with plasma concentrations of IgG at all times (with IgG on d-1: r = 0.61, P = 0.004) and IGF-I on d0 (r = 0.33, P = 0.041) and were negatively correlated with prolactin on d-2 (r = -0.36, P = 0.031). In the multiple regression analysis, variation in colostral IgG concentrations at t0 were explained by plasma concentrations of IgG on d-1 (36%, P = 0.005), prolactin on d-2 (24%, P = 0.019), and progesterone on d-8 (6%, P = 0.118). Amounts of IgG exported in 24 h averaged 157 ± 55 g and this value was partly explained by plasma concentrations of IgG on d-1 (37%, P = 0.004) and progesterone on d-8 (13%, P = 0.044). In conclusion, IgG concentrations in colostrum at the onset of farrowing are related to IgG concentrations in sow plasma in late pregnancy, as previously reported, and IgG transfer into colostrum could be partly regulated by circulating progesterone in sows

Use of an extract (Silymarin) from the plant Silybum marianum to increase circulating concentrations of prolactin in sows

International audienc